SI7710060A8 - Process for obtaining new benzamides - Google Patents

Abstract

Benzamides of the formula <IMAGE> in which X denotes halogen, trifluoromethyl or C3-4-alkyl and Y denotes hydrogen, halogen or nitro, and N-oxides and acid addition salts thereof have useful MAO-inhibiting properties and are accordingly suitable in particular for the treatment of depressive states. These compounds are prepared by condensation of morpholine with appropriately substituted N-(2-haloethyl)benzamides or benzoylaziridines and optionally N-oxidation.

Description

You anic problem

Pina ^ azak refers to a process for the preparation of novel benzamides of the general formula;

γ in which X is halogen, trifluoromethyl or C ₃ -alkyl and Y denotes hydrogen, halogen and nitro, as well as their N-oxides and acid addition salts.

The term halogen refers to these four forms: chlorine, fluorine, bromine iodine. -alkyl residues are normal or branched hydrocarbon residues containing 3 or 4 C atoms, i.e. n-propyl, isopropyl, n-butyl, isobutyl,

1-methylpropyl and t-butyl.

The compounds of formula I are formed with organic or inorganic acids of the addition salt on the nitrogen atom of the morpholine moiety. Examples of such salts are hydrohalides, e.g. hydrochlorides, - phosphates, alkyl and monoaryl sulfonates, such as ethanesulfonates and toluenesulfonates; acetates, citrates, benzoates and torn alike.

Preferred compounds of formula I are those wherein X is halogen. The preferred compounds of formula I are, further, those wherein Y is hydrogen or nitro.

Particularly preferred compounds of formula I should be mentioned; p-Chloro-N- (2-morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, p-iodo-N- (2 -morpholinoethyl) -benzamide and 4-chloro-N- (2-morpholinoethyl) -2-nitrobenzamide.

The preferred compounds of formula I are further alpha, alpha, alpha-trifluoro-N- (2-morpholinoethyl) -p-toluamide, p-butyl-N- (2-morpholinoethyl-yl) -benzamide, 2,4-dichloro-N- (2-Mortolinoethyl) -benzamide and p-chloro-N- (2-morpholinoethyl) -benzamide-N'-oxide.

The state of the art

Japanese Patent 32421/70 describes structurally similar benzamides with analgesic, antispasmodic, sedative and ar.asthetic properties. In contrast, the benzamides of the invention are characterized by MAO inhibitory properties.

Description of the solution

The compounds of formula I as well as their N-oxides and their addition salts can be prepared according to the invention by reacting N- (2-aminoethyl) -morpholine with the compound of the general formula

γ where X and Y have the above meaning as free acid or iii in the form of its reactive functional derivative, and the resulting compound of formula I is optionally oxidized to the corresponding N-oxide or converted to an acid addition salt. As reactive functional derivatives of acids of formulas II, e.g. in consideration of halides, e.g. chlorides, symmetric or mixed anhydrides, esters, e.g. methyl ester, p-nitrophenyl ester or N-hydroxy-succinimidester, azides and amides, e.g. imidazolides or succinimides.

The reaction of N- (2-aminoethyl) -morpholine with an acid of formula II or a reactive derivative thereof may be carried out by methods which are customary in peptide hernia. Thus, e.g. a siobacetic acid of formula II can be reacted with N- (2-aminoethyl) -morpholine in the presence of a condensing agent in an inert solvent. If carbodiimide is used as a condensing agent,

39983

01 ast tehniki- CA .j pr she 1.) with ak belongs to the area 02 anne heniers, more specifically, relationships FIG h procedure to get new ones be .zamida. International Class C 0 ', j 2C5 / 3C, 1: 6LK 31/535.

T »; otherwise: what a problem

Pi she ± azak. refers to the procedure for the dc residence of new benzamides of general fc rmuie:

Y in which X is halogen, trifluoromethyl or c '-alkyl and Y denotes hydrogen, halogen and nitro, as well as their N-oxides and acid addition salts "

The term halogen refers to these four forms: chlorine, fluorine, bromine iodine. -alkyl residues are normal or branched carbonic moieties containing 3 or 4 C atoms, i.e. n-propyl, isopropyl, n-butyl, isobutyl,

1-methylpropyl and t-butyl.

The compounds of formula I are formed with organic or inorganic acid addition salts on the nitrogen atom of the morpholine moiety. Examples of such salts are hydrohalides, e.g. hydrochlorides, - phosphates, alkyl and monoaryl sulfonates, such as ethanesulfonates and toluenesulfonates; acetates, citrates, benzoates and torn alike.

Preferred compounds of formula I are those wherein X is halogen. The preferred compounds of formula I are, further, those in which Y is hydrogen or nitro.

The particular preferred compounds of formula I should include: p-chloro-N- (2-morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide , p-iodo-N- (2-morpholinoethyl) -benzamide and 4-chloro-N- (2-morpholinoethyl) -2-nitrobenzamide.

The preferred compounds of formula I are further alpha, alpha, alpha-trifluoro-N- (2-morpholinoethyl) -p-toluamide, p-t-butyl-N- (2-morpholinoethyl) -benzamide,

2,4-Dichloro-N- (2-morpholinoethyl) -benzamide and p-chloro-N- (2-morpholinoethyl) -benzamide-N'-oxide.

The state of the art

Japanese Patent 32421/70 describes structurally similar benzamides with analgesic, antispasmodic, sedative and ar.asthetic properties. In contrast, the benzamides of the invention are characterized by MAO inhibitory properties.

Description of the solution

The compounds of formula I as well as their N-oxides and their addition salts can be prepared according to the invention by reacting N- (2-aminoethyl) -morpholine with the compound of the general formula

v wherein X and Y have the above meanings, in the form of the free acid or in the form of its reactive functional derivative, and the resulting compound of formula I is optionally oxidized to the corresponding N-oxide or converted to an acid addition salt. As reactive functional derivatives of acids of formula n, e.g. in consideration of thalogenides, e.g. chlorides, symmetric or mixed anhydrides, esters, e.g. methyl ester, p-nitrophenyl ester or N-hydroxy-succinimidester, azides and amides, e.g. imidazolides or succinimides.

The reaction of N- (2-aminoethyl) -morpholine with an acid of formula 11 or a reactive derivative thereof may be carried out by methods customary in peptide chemistry. Thus, e.g. a siobic acid of formula II can be reacted with N- (2-aminoethyl) -morpholine in the presence of a condensing agent in an inert solvent. If carbodiimide is used as a condensing agent,

39983

X as dicyclohexylcarbodiimide, this reaction is conveniently carried out in ethyl acetate, dioxane, methylene chloride, chloroform, benzene, acetonitrile or dimethyliormamide, at a temperature between c -20 C and room temperature, preferably at about 0 C. If phosphorichloride is used as a condensing agent, then the reaction is conveniently carried out in a solvent such as pyridine at a temperature between about 0 C and the reflux temperature of the reaction mixture, preferably at about 90 C. In another embodiment,

N- (2-althinoethyl) -morpholine reacts with one of the aforementioned reactive functional derivatives of an acid of formula II. Thus, for example, a halide may react, e.g. chloride, acids of formula II at about 0 C with N- (2-aminoethyl) -juorpholine in the presence of a solvent, e.g.

diethyl ether, pyridine or water. The compound of formula I can be converted 'to the corresponding N-oxide in a manner known per se, by an oxidizing agent such as hydrogen peroxide or peracid, e.g. persicacetic acid, in a solvent such as glacial acetic acid, at a temperature between about 0 C and 50 C, preferably at room temperature.

The compounds of formula II are known or are analogues of known compounds and can be prepared in a manner known per se. The compounds of formula I, their N-oxides and addition acid salts, are active in preventing monoamine oxidase (MAO). Based on this activity, the compounds of formula I, their N-oxides and their pharmaceutically usable acid addition salts, can be used in the treatment of depressive states.

The activity of preventing MAO compounds according to the invention can be determined using standard methods. Thus, the preparations to be tested were administered to rats p.o. One hour afterwards, the animals were killed and MAO prevention activity in liver homogenates was measured by the method described in Biochem. Pharmacol. ] 2 (1963) 1439-1441. Thus determined activity of several compounds according to the invention as well as their toxicity can be seen from the following Εθςθ values (mol / kg, p.o. on the rat) or. LD ^ -values img / kg, p.o. mouse):

Compound ED ^ LD

p-Chloro-N- (2-morpho- linoethyl) -benzamide alpha, alpha, alpha-trifluoro-N- (2-morpholinoethyl) -p-toluamide 16 5 1000-2000 p-t-butyl-N- (2-morpholinoethyl) -benzamide 16 1250-2500 p-Fluoro-N- (2-morpholinoethyl) -benzamide 11 1250-2500 p-bromo-N- (2-morpholinoethyl) -benzamide 6 1250-2500 p-Iodine-N- (2-morpholinoethyl) -benzamide 4 1250-2500 2,4-Dichloro-N- (2-morpholinoethyl) -benzamide 13 1250-2500

4-Chloro-N - (N - moriolinoethyl) -2-nitrobenzamide 2

Toxicity of p-Chloro-N- (2-morpholinoethyl) -benzamide expressed in LD. (mg / kg, p.o. per rat) is 707 + 55 after 10 days.

The compounds of the formula I according to the invention can be used as medicaments e.g. in the form of pharmaceutical preparations containing them, their N-oxides or their acid addition salts in admixture with one for enteral, e.g. oral or parenteral administration with a suitable pharmaceutical, organic or inorganic inert carrier such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. Acid solutions, suspensions or emulsions. They were eventually sterilized or disposed of. iii contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for change in osmotic pressure

39983 il. buffers. They may also contain dri g «? therapeutically valuable substances. Suitable pharmaceutical dosage forms include about 1 to 100 mg of foimule 1 compound, its N-oxide or its pharmaceutically usable acid addition salt. The preferred oral dosage range is at about 0.1 mg / kg to about 5 mg / kg per day. However, the said area may extend upwards or downwards, but according to the individual need and transcript of the expert. An oral application has been set up.

Example 1 g of p-chlorobenzoyl chloride was added dropwise with stirring and cooling with ice water to a solution of 26 g of N- (2-aminoethyl) -morpholine in 200 ml of pyridine. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was re-evaporated twice with 200 ml of toluene. The solid residue was then taken up with 300 ml of ice water and 300 ml of methylene chloride and basified with 3 N sodium hydroxide solution. The phases were separated and the methylene chloride extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from isopropanol. 41.5 g of p-chloro-N- (2-morpholinoethyl) -benzamide are obtained, m.p. 137 C.

The following compounds of alpha, alpha, alpha-trifluoro-N- (2-morpholinoethyl) -p-toluamide, m.p. 120-121 ° C; p-t-butyl-N- (2-morpholinoethyl) -benzamide, m.p. 94 ° C;

p-Fluoro-N- (2-morpholinoethyl) -benzamide, mp. 136-137 DEG C. p-bromo-N- (2-morpholinoethyl) -benzamide, mp. 140-141 ° C?

p-Iodine-N- (2-morpholinoethyl) -benzamide, mp. 160 ° C, 2,4-Dichloro-N- (2-morioolinoethyl) -benzamide, m.p. 120 ° C.

Example 2 g of N, N-aminoethyl) -morpholine, while stirring and cooling with ice water, was added dropwise a solution of 17.5 g of p-chlorobenzoyl chloride in 100 ml of diethyl ether. After complete curing, the reaction mixture was further stirred for 2 hours at room temperature. The crystalline product was separated by filtration and washed with diethyl ether. Recrystallization from isopropanol gives 9.1 g of p-chloro-N- (2-mortolinoethyl) -benzamide hydrochloride, m.p. 2Q7-208 ° C.

4-Chloro-N- (2-morpholinoethyl) -2-nitrobenzamide hydrochloride, m.p. 208 ° C.

Example 3

10.5 g of p-chlorobenzoic acid anhydride are added in portions, a solution of 4.55 g of N- (2-aminoethyl) -morpholine in 100 ml of pyridine, with stirring and cooling with ice water. After completing the addition of the reaction mixture. stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was re-evaporated twice with 100 ml of toluene each. The solid residue was taken up in 200 ml of water with 200 ml of methylene chloride and basified with

N sodium hydroxide solution. The phases were separated and the methylene chloride extra was washed with water, dried over sodium sulfate and evaporated. The residue t was crystallized from isopropanol. 4.5 g of p-chloro-N- (2-morpholinoethyl; -benzamide are obtained which is identical to the product obtained in example 1.

Example 4

5.3 ml of hydrochloric acid ethyl ester were added dropwise to a solution of 6.6 p-chlorobenzoic acid and 7.6 triethylamine in 150 ml of acetone while stirring and cooling with ice-water. Leave for 1 hour at 0 c, drop the solution

6.5 g of N- (2-aminoethyl) -morpholine in ml of acetone and stirred at room temperature overnight. The reaction mixture was then concentrated, resid. to stand for 2 hours in the filtration refrigerator. The filtrate was evaporated to dryness, the residue was taken up in 250 ml of water and ml of methylene chloride. The methylene chloride extract was separated from above with sodium sulfate and the residue was recrystallized.

39983 isopropanol. 7.8 g of p-chloro-N- (2-morpholinotyl) -benzamide kc is obtained, and is identical to the product obtained in example 1.

Example 5

8 ,. g of p-chlorobenzoic acid methyl ester and 6.25 g of N- (2-aminoethyl) -morpholine were stirred for 6 hours at 120 C. The reaction mixture was cooled to room temperature, mixed with 40 ml of diethyl ether and allowed to stand overnight in the refrigerator. The crystalline product was separated by filtration, washed with diethyl ether and recrystallized from isopropanol. 2.6 g of p-chloro-N- (2-morpholinoethyl) -benzamide are obtained which is identical to the product obtained in Example 1.

Example 6

A solution of 2.6 g of N- (2-aminoethyl) -morpholine in 100 ml of tetrahydrofuran is mixed with 5.55 g of p-chlorobenzoic acid p-nitrophenyl ester and allowed to stand at room temperature. The reaction mixture was then evaporated to dryness and the residue was taken up in 200 ml of methylene chloride. The ethylene chloride solution was washed three times with 50 ml of 3% sodium hydroxide solution each and twice with 50 ml of water until neutral, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from. of isopropanol. 3.1 g of p-chloro-N- (2-morpholinoethyl) -benzamide are obtained which is identical to the product obtained in Example 1.

Example 7

A solution of 1.3 g of N- (2-aminoethyl) -morpholine in 100 ml of dioxane was mixed with 2.4 g of p-chloro-N- (ρ-chlorobenzoyl) -succinimide and stirred at room temperature overnight. The reaction mixture was then evaporated to dryness. The oily residue was mixed with 50 ml of ice water and the crystallized mixture was allowed to stand overnight in the refrigerator. The product was separated by filtration, washed with cold water, dried and recrystallized from isopropanol. 0.65 g of p-chloro-N- (2-morpholinoethyl) -benzamide is obtained which is identical to the product obtained in Example 1.

Example 8

7.8 g of p-chlorobenzoic acid and 6.5 g of N- (2-aminoethyl) -morpholine are dissolved in 150 m pyridine, at 4 C mixed with

10.5 g of dicyclohexylcarbodiimide and stirred for 4 h at 4 C overnight at room temperature. The reaction mixture is then poured into 1 liter of water and the rewarded dicyclohexylurea is filtered off. The filtrate is extracted twice with ρο 20 ml of methylene chloride. The methylene chloride extract was dried over sodium sulfate, evaporated to dryness and the residue was recrystallized from isopropanol. 0.6 g of p -chloro-N- (2-morpholinoethyl) -benzamide are obtained which is identical to the product obtained in Example 1.

Example 9

5.2 g of N- (2-aminoethyl) -morpholine in 80 ml of pyridine was stirred at -5 for 15 minutes and mixed with 2.8 g of phosphorus trichloride in 20 ml of pyridine.

The reaction mixture was stirred for 30 min. mixes on

-5 C and 90 min. at room temperature.

Then 3.1 g of p-chlorobenzoic acid are added and the reaction mixture is heated to 90 for 3 h. The reaction mixture was evaporated to dryness and the residue was re-evaporated twice with 100 ml of toluene each. The solid residue was taken up in 100 ml of methylene chloride and 100 ml of ice water and the mixture was basified with 3 n sodium hydroxide solution. The phases were separated and the methylene chloride extract was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from isopropanol. 1.3 g of p-chloro-N- (2-morpholinoethyl) -benzamide are obtained which is identical to the product obtained in Example 1.

Example 10

To a solution of 10 g p-chloro-N- (2-morpholinoethyl) -benzamide in 50 ml glac. of acetic acid was added 25 ml of 30% hydrogen peroxide and allowed to stand for 48 h at room temperature.

39983 temperature. Then the reaction mixture was evaporated:. to dryness and the residue is chromatographed on a silica gel column with a mixture of chloroform and ethanol. The pure fractions were evaporated and the residue was pre-crystallized from ethyl acetate-isopropyl ether. 6.8 g of ρ-chloro-N- (2-morpholinoethyl) -benzamide - Ν'-oxide are obtained, mp. 201 C (decomposition.).

Example 11

Pills of the following formulation are known per se: p-chloro-N- (2-morpholinoethyl) benzamide 50 mg milk sugar 95 mg corn starch 100 mg talc 4,5 mg magnesium stearate 0,5 mg weight of one tablet 250, 0 mg g of p-chlorobenzoyl chloride was added dropwise with stirring and cooling with ice-water to a solution of 26 g of N- (2-aminoethyl-morpholine in 200 ml of pyridine. The reaction mixture was then stirred overnight at room temperature. to dryness and the residue was re-evaporated twice with 200 ml of toluene, then the solid residue was taken up with 300 ml of ice water and 300 ml of methylene chloride and basified with 3 N sodium hydroxide solution The phases were separated and the methylene chloride extract was washed with water , dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from isopropanol to give 41.5 g of p-chloro-N- (2-morpholinoethyl) -benzamide, m.p. 137 C.

Claims (1)

PATENT APPLICATION 1. The following procedure for the preparation of new benzamides of the general formula: in which X is halogen, trifluoromethyl or C1-6alkyl and Y represents hydrogen, iii X and Y denote it by chlorine as well as their N-oxides and pharmaceutically acceptable salts with acids, wherein N- (2-Aminoethyl) -morpholine is treated with the compound in general. of the formula wherein X and Y have the above meaning, in pyridine in the presence of dicyclohexylcarbodiimide at a temperature between about 0 C and room temperature or in the presence of phosphorous chloride at a temperature of about 90 ° C, or with a halide, symmetric anhydride p-nitrophenyl ester or succinimide of the compound of formula II, iii by the compound of formula III Y in which X and Y have the above meanings, derived from the compound of formula II and chloromic acid ethyl ester, at a temperature between about 0 C and room temperature in pyridine, diethyl ether, tetrahydrofuran, dioxane or acetone, or with methyl ester of the compound of formula II in the absence of a solvent at a temperature of about 120C, and if desired, the resulting compound of formula I is oxidized with hydrogen peroxide in glacial acetic acid at a temperature around room temperature to the corresponding N-oxide, or converted to a pharmaceutically acceptable acid addition salt .